Real World Effectiveness of Antipsychotic Treatment on Functional Outcomes Over Ten Years: A National Cohort of Patients in Denmark with Schizophrenia

Abstract Background Antipsychotic medications are recommended for managing schizophrenia spectrum disorders, yet their long-term effects on functional recovery remain unclear. Existing evidence is conflicting, often derived from between-subject comparisons vulnerable to confounding by indication. Methods We conducted a nationwide register-based cohort study of 65,630 individuals with incident schizophrenia spectrum disorders in Denmark (1998-2023). We modelled antipsychotic exposure against ‘productive engagement’ (employment or education). We employed two distinct analytical approaches to separate causal from prognostic associations: (1) Within-subject stratified Cox models with time-varying covariates, where patients served as their own controls to eliminate time-invariant confounding; and (2) Fine-Gray competing risks models using a between-subject design with baseline exposure, accounting for mortality and emigration. Findings Over 26.9 million person-weeks, the overall productive engagement rate was 48.2%. Integration of hospital pharmacy data revealed a 6.1% exposure misclassification bias in previous studies relying solely on community records. The primary within-subject analysis revealed significant temporal heterogeneity: medication use was associated with reduced engagement rates in the acute (0–2 years: HR 0.908) and consolidation phases (2–5 years: HR 0.946), but reversed to a positive association in the maintenance phase (5+ years: HR 1.019). In contrast, the between-subject Fine-Gray model yielded a null result (SHR 1.002, 95% CI 0.988–1.015), failing to detect these phase-specific dynamics. Interpretation Within-subject modelling reveals that antipsychotic treatment involves a functional trade-off: it is associated with a transient reduction in engagement rates during the early ‘consolidation’ phase (2–5 years), followed by stabilisation and potential benefit in the maintenance phase (5+ years). The null result in standard between-subject (Fine-Gray) analysis likely reflects residual confounding by indication and exposure misclassification, highlighting the necessity of within-person designs to unmask the true stage-specific impact of pharmacotherapy on vocational recovery. Funding None directly for this study. Danmarks Nationalbank funded the research visit that facilitated this collaboration.